The sigma-2 receptor is a promising target for cancer therapy due to its overexpression in multiple malignancies including: breast, pancreatic, ovarian, lung, renal, melanoma, neuroendocrine and colon. The molecular function of the sigma-2 receptor has been defined through pharmacological studies that have validated it as a biomarker that can be utilized to non-invasively measure the proliferative status of tumors. During cell proliferation the sigma-2 receptor is overexpressed by a factor of 10 compared with quiescent or nonproliferative cells. Confocal microscopy studies have shown the subcellular localization of sigma-2 receptors on cell membrane, lysosomes, endoplasmic reticulum, and mitochondria.
Sigma-2 ligands, classified as azabicyclononane derivatives, have been shown to undergo rapid internalization and are capable of inducing caspase dependent and independent cell death pathways. More recently, the molecular identity of the sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1), providing new insight and potential for further defining its biological, pharmacological and molecular properties. Three classes of sigma-2 ligands have been characterized pharmacologically through caspase-3/7 activation as agonist, partial agonist or antagonist. Azabicyclononane and tropane analogs induce or partially induce downstream caspase 3/7 activation, and therefore are considered agonist to the sigma-2 receptor. The benzamide class of ligands acts as antagonists, unable to induce caspase activity, and is believed to interact with binding sites on the surface membranes, although passive diffusion across the cell membrane has not been evaluated.
Sigma-2 antagonists have been historically developed as imaging agents due to their safe toxicity profile and high affinity and selectivity for the sigma-2 receptor, as well as fast tumor targeting and clearance in vivo. Numerous selective sigma-2 ligands have been reported, however, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-F-fluoromethoxy)-5-methylbenzamide is the only diagnostic imaging agent used clinically in a research setting. Other sigma-2 ligands have been applied in chemosensitization and the targeted delivery of cancer therapeutics showing a beneficial therapeutic response in pre-clinical models. Currently, only sigma-2 agonist conjugates have been used as therapeutics. This has been most likely due to the lack of cytotoxicity observed with sigma-2 antagonists and evidence to support whether this class of ligands enters the cell, which is an important characteristic for the therapeutics ability to reach the site of action.
